The present invention generally relates to treatment of ocular diseases and disorders and more specifically relates to a method for treatment of aqueous deficient dry-eye state, phacoanaphylaxis endophthalmitis and uveitis using certain cyclosporin derivatives.
The exposed part of a normal eye is covered by a thin tear film. The presence of a continuous tear film is important for the well-being of the corneal and conjunctival epithelium and provides the cornea with an optically high quality surface. In addition, the aqueous part of the tear film acts as a lubricant to the eyelids during blinking of the lids. Furthermore, certain enzymes contained in the tear fluid, for example immunoglobin A, lysozyme and beta lysin, are known to have bacteriostatic properties.
A sound lacrimal system functions to form and maintain a properly structured, continuous tear film. The lacrimal apparatus consists of the secretory system (the source), the distribution system, and the excretory system (the sink). In the secretory system, aqueous tears are supplied by main and accessory lacrimal glands.
The bulk of the tear film is made of such aqueous tear. The continuous production and drainage of aqueous tear is important in maintaining the corneal and conjunctival epithelium in a moist state, in providing nutrients for epithelial respiration, in supplying bacteriostatic agents and in cleaning the ocular surface by the flushing action of tear movement.
Abnormalities of the tear film include an absolute or partial deficiency in aqueous tear production (keratoconjunctivitis sicca, or KCS).
In relatively mild cases, the main symptom of KCS is a foreign body sensation or a mild scratchiness. This can progress to become a constant, intense burning or irritative sensation that can be debilitating to a patient.
More severe forms can progress to the development of filamentary keratisis, a painful condition characterized by the appearance of numerous strands or filaments attached to the corneal surface. Evidence suggests that these filaments represent breaks in the continuity of normal corneal epithelial cells. The shear created by lid motion pulls these filaments, causing pain. Management of this stage of KCS is very difficult.
A frequent complication of KCS is secondary infection. Several breakdowns in the eye""s normal defense mechanisms seem to occur, presumably attributable to a decrease in the concentration of antibacterial lysozyme in the aqueous tears of a patient suffering from KCS.
Although KCS can develop in the absence of any other overt system abnormality, there is a frequent association of KCS with systemic disease. KCS can occur as part of a larger systemic involvement known as Sjogren""s syndrome. This classically consists of dry eyes, dry mouth and arthritis.
Histologically, in KCS (as part of Sjogren""s syndrome or in isolation), the initial changes seen in the lacrimal glands are those of focal lymphocytic and plasma cell infiltrates associated with degeneration of glandular tissue. These changes resemble those seen in autoimmune disease in other tissue, giving rise to the speculation that KCS has an autoimmune basis.
Sjogren""s syndrome is recognized as an exocrine gland dysfunction. Characteristically, the lacrimal glands show a mononuclear cell infiltration that ultimately leads to destruction of the glandular structure.
Conventional treatment of KCS is symptomatic. Normally, aqueous-deficient dry eye states are treated by supplementation of the tears with artificial tear substitutes. However, relief is limited by the retention time of the administered artificial tear solution in the eye. Typically, the effect of an artificial tear solution administered to the eye dissipates within about thirty to forty-five minutes. Thus, the effect of such products, while soothing initially, does not last long enough. The patient is inconvenienced by the necessity of repeated administration of artificial tear solution in the eye as needed to supplement the normal tears. Moreover, such treatment merely acts to alleviate the symptoms of the dry eye state and does not cure any underlying disorders or causes of the dry eye state.
Histologic studies of the lacrimal glands in patients suffering from Sjogren""s syndrome have shown some evidence of lacrimal gland inflammation. Such inflammation may be simply due to the normal aging of the patient. It has been suggested that the use of anti-inflammatory agents might serve to decrease the glandular inflammation. The systemic use of corticosteroids has been advocated in these conditions. However, the merit of systemic corticosteroids in dry eye states has not been established. In most dry eye cases, the hazards of long term use of anti-inflammatory agents would seem to outweigh their potential merit.
Surgical procedures have also been suggested in the management of dry eye states. Where there has been significant conjunctival destruction, mucous membrane transplants have been advocated. It has also been suggested that parotid (saliva) duct transplantation can be useful in the management of dry eyes. However, surgical alterations to combat dry eye conditions constitute a dramatic remedy and any benefit resulting from these alterations is questionable.
It has also been suggested to administer orally a dilute solution of pilocarpine to stimulate the autonomic nervous system to effect increased aqueous tear production. This method of treatment has not met with universal favor because of many unpleasant side effects of ingested pilocarpine.
Animal models of Siogren""s syndrome have been instrumental in basic ophthalmic research. A Sjogren""s-like disease has been found in dogs with systemic luperythematosus. This disease, which may be referred to as canine KCS, is a common, chronic, progressive, and potentially blinding disease. A continuum of corneal and conjunctival lesions ensues from the dry eye state. The cause of canine KCS is often not identified. Usually canine KCS is not an isolated ophthalmic disease. It has been speculated in Kaswan et al., Am. J. Vet. Res. 46, 376-383 (1985), that most cases of canine KCS occur via autoimmune mechanisms.
Other diseases of the eye include phacoanaphylactic endophthalmitis and uveitis. These diseases can be located throughout the eye, in both the posterior and anterior chambers of the eye as well as in the vitreous body.
Uveitis, the inflammation of the uvea, is responsible for about 10% of the visual impairment in the United States. Phacoanaphylactic endophthalmitis is a human autoimmune disease.
Panuveitis refers to inflammation of the entire uveal (vascular) layer of the eye. Posterior uveitis generally refers to chorioentinitis, and anterior uveitis refers to iridocyclitis. The inflammatory products (i.e. cells, fibrins, excess proteins) of these inflammations are commonly found in the fluid spaces if the eye, i.e. anterior chamber, posterior chamber and vitreous space as well as infiltrating the tissue intimately involved in the inflammatory response. Uveitis may occur following surgical or traumatic injury to the eye; as a component of an autoimmune disorder, i.e. rheumatoid arthritis, Behcet""s disease, ankylosing spondylitis, sarcoidosis; as an isolated immune mediated ocular disorder, i.e. pars planitis, iridocyclitis etc., unassociated with known etiologies; and following certain systemic diseases which cause antibody-antigen complexes to be deposited in the uveal tissues. Together these disorders represent the non-infectious uveitities.
The normal eye is protected from immune surveillance by blood barriers which do not allow free migration of cells or proteins into the eye. When the eye is injured or when vasculitis occurs, the internal ocular structures are exposed to the general immune system and frequently illicit autoinmmune responses.
Phacoanaphylaxis is a severe form of uveitis in which the lens in the causative antigen. The lens proteins are normally secluded by the lens capsule since before birth. When these proteins are released into the eye by injury or by surgery or occasionally during cataract development, they can become intensely antigenic and incite an autoimmune response. If the response is moderate it is seen as chronic uveitis. If it is very fast in progression the eye becomes seriously inflamed in all segments. This latter response is named phacoanaphylaxis.
Methylthio-substituted cyclosporin A and other alkylthio-substituted cyclosporin A derivatives have been described in PCT application Nos. 98-379455, 98-379456 and 98-379457 and have been found to be active against certain retroviruses, especially AIDS (acquired immunodeficiency syndrome) and ARC (AIDS-related complex) when administered orally, parenterally, rectally or by inhalation. In addition, they have generally been found to have only a very weak immunosuppressant action, and to show anti-retroviral activity at non-cytotoxic and non-cytostatic concentrations. These compounds are claimed to have a synergistic action with other agents active against retrovirus (such as inhibitors of reverse transcriptase, protease, integrase, HIV replication and nucleocapside).
Although these compounds are claimed to be effective against retroviruses, it has not been heretobefore suggested to administer any of these compounds to a patient in order to treat the ocular diseases described hereinabove. The present invention provides a method of treating a patient affected with such an ocular disorder by topically applying one or more of these compounds to the diseased eye.
Accordingly, a method in accordance with the present invention generally comprises the step of administering to an eye, a therapeutically effective amount of a compound selected from the group consisting of ((R)-methylthio-Sar)3-(4xe2x80x2-hydroxy-MeLeu) cyclosporin A, ((R)-(Cyclo)alkylthio-Sar)3-(4xe2x80x2-hydroxy-MeLeu)4-cyclosporin A, and ((R)-(Cyclo)alkylthio-Sar)3-cyclosporin A derivatives of the formulas described below, in order to treat an ocular disorder in the eye, for example, an aqueous deficient dry eye state, uveitis, or phacoanaphylactic endophthalmitis. The cyclosporin A derivatives utilized in the method of the present invention are disclosed in published PCT patent applications Nos. 98-379455, 98-379456, and 98-379457, entitled New Methylthio-substituted Cyclosporin A derivativexe2x80x94Active Against Retro-viruses and Having Only Weak Immunosuppressant Action, Used in Treatment of AIDS, New Alkylthio-substituted Cyclosporin A derivativesxe2x80x94Active Against Retro-viruses and Having Only Weak Immunosuppressant Action, Used in Treatment of AIDS, and New Alkylthio-substituted Cyclosporin A derivativesxe2x80x94Active Against Retro-viruses and Having Only Weak Immunosuppressant Action, Used for Treating AIDS, respectively, which are hereby incorporated by reference in their entirety.
The objects and advantages of the present invention will be more clearly understood and appreciated with reference to the following detailed description.